1. Metabolic Changes of Drugs
Prof. Faris T. Abachi ( PHD Pharmacy)
3rd Year Pharmacy
2013

2. Susceptibility to Hydrolysis
Hydrolytic Reactions
Hydrolyzes (adds water to) esters and amides and their isosteres; the OH from water ends up on the carboxylic acid (or its isostere) and the H in the hydroxy or amine
Enzymes: Non-microsomal hydrolases; however, amide hydrolysis appears to be mediated by liver microsomal amidases, esterases, and deacylases
Electrophilicity of the carbonyl carbon, Nature of the heteroatom, substituents on the carbonyl carbon, and substituents on the heteroatom influnce the rate of hydrolysis
In addition, Nucleophilicity of attacking species, Electronic charge, and Nature of nucleophile and its steric factors also influence the rate of hydrolysis
Table: Naming carbonyl - heteroatom groups R1 R2
Name
Susceptibility to Hydrolysis C O
Ester
Highest S
Thioester
Carbonate N
Amide
Carbamate
Ureide
Lowest

3. The Reactions Ester hydrolysis Amide hydrolysis (slower)
Carbonate hydrolysis
Carbamate hydrolysis
Urea hydrolysis
Hydrazide hydrolysis

4. Drug Examples
Lidocaine

5. Stereoselectivity of Hydrolysis
Etomidate (Amidate, hypnotic): R-(+)-isomer is more rapidly hydrolyzed, but S-(-)-isomer is more rapidly hydroxylated.

6. The Concept of Prodrugs and Antedrugs
Prodrug: Need metabolic activation
Antedrug: Active drug that is quickly inactivated thereby minimizing systemic effects

7. Prodrugs and Related Terms
Albert in 1958 coined the term prodrug to refer a pharmacologically inactive compound that is metabolically activated in the mammalian system
Hard Drugs are not susceptible to metabolic or chemical transformation, have high lipid solubility and thus accumulation or high water solubility
Celecoxib: t1/ h in humans t1/2 ca. 680 h (Liver toxicity)
Soft drugs are active compounds that after exerting its action undergo inactivation to give a nontoxic product. Indeed soft drugs are a group of modified compounds that are also designed to delivery the drugs in to the brain (the chemical delivery system). Bodor coined the term. Ce

8. Basic Concepts of Prodrugs
Carrier-linked prodrugs: a pro-moiety is attached, which is not necessary for activity but may impart some desired property to the drug, such as increased lipid or water solubility, or site-directed delivery
Advantages may include:
increased absorption
alleviation of pain at the site of injection if the agent is given parenterally
elimination of an unpleasant taste associated with the drug
decreased toxicity
decreased metabolic inactivation
increased chemical stability
prolonged or shortened action
Bioprecursor prodrugs contain no pro-moiety but rather rely on metabolism to introduce the functionality necessary to create an active species

9. Prodrug: Prednisolon Hemisuccinate Sodium Salt
Prodrug: Chloramphenicol Hemisuccinate Na Salt
Prodrug: Prednisolon Hemisuccinate Sodium Salt
Inactive as it is and activated by hydrolysis by plasma esterases to chloramphenicol/ prednisolon
Increased water solubility for parenteral administration, which otherwise would precipitate and cause pain by damaging surrounding tissues
Prodrug: Chloramphenicol Palmitate
Prodrug: Clindamycin Palmitate
Inactive as it is; activated by hydrolysis by intestinal esterases to chloramphenicol/ clindamycin
Minimize their bitter taste and improve their palatability in pediatric liquid suspensions

10. Prodrugs of Functional Groups
Carboxylic acids and alcohols: Most common
Amines and azo linkages: Not been used much
Carbonyl compounds: Not found to be used widely

11. Carboxylic Acids and Alcohols
Converted to ester prodrugs which are often hydrolyzed to active drug by different types of esterase enzymes:
Ester hydrolase
Lipase
Cholesterol esterase
Acetylcholinesterase
Carboxypeptidase
Cholinesterase
Microflora in the gut
Manipulation of steric and electronic properties of promoiety allows control of rate and extent of hydrolysis

12. Advantage of Prodrug Formation I: Increased absorption of hydrophilic drugs by making less hydrophilic or more lipophilic
Prodrug of Epinephrine: Dipivefrin
More lipophilic, thus achieve higher intraocular concentration
Hydrolysis occur in cornea, conjunctiva, and aqueous humor after ophthalmic application

13. Not all carboxylic esters hydrolyzed in vivo where double ester approach is used